The Hereditary Features Of Epilepsies With SCN1A Mutations

Background: Mutations in the SCN1A gene have been identified in epilepsy patients with great variations in phenotype, in both familial and sporadic cases. In the majority of cases, severe myoclonic epilepsy in infancy (SMEI) is caused by de novo truncating or splice-site mutations of SCN1A, whereas generalized epilepsy with febrile seizures plus (GEFS+) is a familial disorder mostly associated with missense mutations, suggesting that the severity and genotype are associated with hereditary features.Methods: We performed a meta-analysis of SCN1A mutations that have been identified in patients with epilepsy to investigate the hereditary feature of each phenotype and a possible genotype-inheritance correlation. Results: The frequency of familial cases was 11.2% in epilepsies caused by SCN1A mutations and negatively correlated with severity of phenotypes and genotypes. Familial cases was 85.7% in GEFS+, 62.5% in partial epilepsy with febrile seizures, 12.5% in borderline SMEI, and 7.5% in SMEI (p<0.01). Familial cases 19.1% in patients with missense, 7.7% with splice-site, 4.9% with truncating mutations, and 2.4% with genomic rearrangements (p<0.01); more frequently associated with missense mutations in the voltage sensors of Nav1.1 (34.3%). Contrary to the large variation in clinical manifestations, the penetrance did not differ in each phenotype, suggesting a dominant effect of SCN1A mutations in causing epilepsies. Mosaicism accounted for 52.8% of the origin of familial SMEI.Conclusions: The hereditary features of epilepsies with SCN1A mutations differed in each phenotype and were associated with the genotypes. The frequent de novo mutations suggest a need for clinical attention to sporadic milder cases.